Islet transplantation is the most specific therapy for restoration of euglycemia in patients with type 1 diabetes. Despite the recent success of clinical islet transplantation, achievement of long-term allograft survival remains an elusive goal even in the presence of chronic immunosuppression. Therefore, a major objective in advancing the field of islet transplantation is to develop novel immune intervention strategies capable of inducing permanent allograft survival while eliminating the chronic use of immunosuppressive agents. Presently the mainstay of immunosuppressive therapy for islet transplantation includes induction with T lymphocyte specific antibodies followed by maintenance with T cell specific pharmacological agents. This 'T-cell focused' approach is based on the well-established function of T lymphocytes as the effector population responsible for graft rejection. Notwithstanding the logic of this approach, both clinical and experimental data clearly indicate that T cell directed immunosuppression fails to promote immunological tolerance to islet allografts. Here, we suggest that a more balanced consideration of the components of the adaptive immune response to allografts provides a strong rationale for an integrated approach to immunosuppression: one including both the T- and B- lymphocyte compartments. It is well established that host B lymphocytes, in addition to the alloreactive T cell compartment, mount a robust immune response against donor alloantigens following transplantation. Despite this well-recognized feature of the alloimmune response, the B lymphocyte compartment has been largely neglected as a target of induction immunotherapy. Our preliminary exploratory studies have indicated that host B lymphocytes play a key role as antigen presenting cells in the pathogenesis of acute allograft rejection. Furthermore, our pilot studies in non-human primate recipients suggest that transient B lymphocyte depletion using an anti-CD20 mAb (i.e., Rituxan) at the induction phase promotes long-term islet allograft survival, while minimizing the need for chronic immunosuppression. These results have compelled us to propose a more balanced approach to induction immunotherapy by integrating both T- and B- lymphocyte specific antibodies (i.e., Thymoglobulin and Rituxan) into a tolerogenic regimen. In this project, we will determine the efficacy of such an induction immunotherapy regimen in a rigorous preclinical model and investigate its mechanistic basis in promoting islet allograft survival in non-human primates. Our overall contention is that interruption of T- and B- lymphocyte function during the induction phase represents a novel and potentially powerful means of promoting immunological tolerance to islet allografts.